Factor XI/XIa inhibitors versus direct oral anticoagulants in atrial fibrillation with stroke risk: a GRADE-assessed meta-analysis of randomized controlled trials

Abstract

Direct oral anticoagulants (DOACs) prevent stroke in atrial fibrillation (AF) but are associated with an increased risk of major bleeding. Factors XI/XIa (FXI) inhibitors, such as Abelacimab and Asundexian, offer a promising alternative. This meta-analysis compares FXI/XIa inhibitors' safety and efficacy versus DOACs in AF with stroke risk. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed from PubMed, Scopus, Cochrane, and Web of Science up to March 2025. The analysis presented risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using RevMan v5.4. Three RCTs involving 16,852 patients were included, with 8777 (52.1%) receiving FXI inhibitors which significantly reduced the risk of major bleeding (0.4% vs. 1.0%, RR 0.31, 95% CI 0.21-0.46, p < 0.00001) and minor bleeding (3.3% vs. 4.7%, RR 0.66, 95% CI 0.47-0.93; p = 0.02) compared with DOACs. However, FXI inhibitors were associated with a significantly higher risk of stroke or systemic embolism (1.4% vs. 0.4%, RR 3.17, 95% CI 2.18-4.62, p < 0.00001). Safety outcomes showed no difference in total adverse events (AEs) (p = 0.91), serious AEs (p = 0.4768), and all-cause mortality (p = 0.15). In conclusion, current evidence suggests that FXI inhibitors significantly reduce major and minor bleeding events in AF patients at risk of thromboembolic disorders compared to DOACs. However, they are associated with a significant increase in stroke or systemic embolism risk. Further large-scale RCTs are needed to confirm these findings.

Keywords: Atrial fibrillation; Direct oral anticoagulants; Factor XI inhibitors; Major bleeding; Stroke.